Medical knowledge | Diseases » Rao-Johari-Cros - Hepatitis C seroprevalence and HIV coinfection in sub-Saharan Africa, A Systematic Review and Meta-analysis

Source: http://www.doksinet Hepatitis C seroprevalence and HIV co-infection in subSaharan Africa: a systematic review and meta-analysis *Bhargavi V Rao1,2, MRCP, Nur Johari2, BSc, Phillip du Cros1, MRCP, Janey Messina4, PhD, Nathan Ford2,3*, PhD Graham S Cooke2* PhD 1 Manson Unit, Médecins Sans Frontières (MSF), London, UK 2 Division of Infectious Diseases, Imperial College London, UK 3 Médecins Sans Frontières (MSF), Geneva, Switzerland 4 Spatial Epidemiology and Ecology Group, Department of Zoology, University of Oxford, UK *contributed equally to this work Total word count: 2998 *Corresponding authors: bhargavi.rao@londonmsforg and g.cooke@imperialacuk Address: Manson Unit, MSF-UK, 67-74 Saffron Hill, London EC1N 8QX, UK Tel: +44 (0)2074046600 Fax: +44 (0)2074044466 Oxford 1 Source: http://www.doksinet Abstract Background An estimated 150 million people worldwide have been infected with hepatitis C virus (HCV). HIV co-infection accelerates the progression of HCV and

represents a major public health challenge. In a systematic review and meta-analysis, we aimed to determine the epidemiology of HCV and the prevalence of coinfection with HIV in sub-Saharan Africa. Methods We included HCV seroprevalence data from 2002 to end of 2014 relating to the WHO defined regions of sub-Saharan Africa. We estimated pooled regional prevalence estimates using a DerSimonian-Laird random effects model. Data were further stratified by risk factor and HIV status. Findings From 213 studies, we identified 287 separate cohorts with a total of 1,198,167 individuals. The mean pooled HCV seroprevalence from all cohorts was 3% (95%CI: 2.9-31) The pooled HCV seroprevalence was 2.7% (95%CI: 25-28) across all 185 low risk cohorts; 3% (95%CI: 2.2-38) in antenatal groups, 2% (95%CI: 192 Source: http://www.doksinet 2.1) among blood donors but 69% (95%CI: 61-75) in other general population cohorts. The pooled seroprevalence of HCV across all high-risk groups was 11.9% (95%CI:

71-167) and 10% (95%CI: 6.8-131) in patients with liver disease 101 cohorts included HIV-positive samples tested for HCV (42,648 individuals) with pooled seroprevalence of 5.7% (95%CI: 49-66) Interpretation We found a high seroprevalence of HCV across populations of sub-Saharan Africa including within HIV-positive adults, with evidence of regional variation in the general population. Monitoring antenatal HCV prevalence may be a helpful indicator of population trends in HCV infection. There are limitations to available data with a need for larger survey studies. Access to prevention and treatment needs to be improved for both mono-infected and coinfected individuals. Funding None. 3 Source: http://www.doksinet Introduction Hepatitis C virus (HCV) is estimated to have infected 130-150 1,2 million individuals worldwide Global Burden of Disease and contributes significantly to the 3,4 . There is no vaccine close to market for HCV, hence control of the epidemic rests on

preventative measures - including the screening of blood products, opiate substitution, and needle exchange - and treatment to prevent progression to cirrhosis and hepatocellular carcinoma. Until recently, the complexity of HCV therapy was a barrier to widespread treatment; standard therapy involved injectable pegylated interferon and ribavirin tablets, in a long and complex regimen dependant on viral genotype and requiring frequent monitoring 5,6 . HCV management has been revolutionised by recently licensed directly acting antiviral agents (DAAs), including protease inhibitors, NS5B inhibitors (e.g sofosbuvir 7,8 ) and NS5A inhibitors (e.g ledipasvir and daclatasvir), which allow shortened treatment with improved success rates without the use of interferon 9,10 . The new treatments have the potential to reduce substantially the clinical and operational barriers to treatment throughout the world, provided they are accessible and affordable 6,11 . 4 Source:

http://www.doksinet Accurate epidemiological information is essential to inform treatment and control priorities at national and regional levels. In particular, data are needed on the burden of co-infection with HIV given the poorer outcomes for HCV in this population 12. There is paucity of such data in many regions, particularly parts of sub-Saharan Africa, to some extent due to the relative public health importance of HCV infection being only recently recognised 3 . A review of HCV epidemiology in sub-Saharan Africa published in 2002 estimated the overall prevalence of HCV to be 3%, with significant regional variation 13 . A further review of the association of HIV and hepatitis B and C showed a relative risk of HIV coinfection of 1.6 (95%CI: 105-245) 14 . However, both analyses found little data on the prevalence of HIV-HCV co-infection, which is critical to the current policy debate surrounding expansion of HCV treatment. In a systematic review and meta-analysis of

studies published since 200213, we aimed to determine the seroprevalence of HCV and the prevalence of HCV/HIV co-infection across sub-Saharan Africa, addressing the availability and type of data included and categorising cohorts by risk. 5 Source: http://www.doksinet Methods Inclusion criteria Countries included in the study were limited to countries in subSaharan Africa grouped according to WHO Africa regions. In order to directly compare results with earlier published analyses, six countries were excluded (Algeria, Cape Verde, Comoros, Mauritius, Sao Tome & Principe, and Seychelles). Three countries not listed in the WHO regional list – Sudan (and South Sudan after 2012), Djibouti, and Somalia were included in the study. Studies published in English and French were included. Studies were not rejected on the basis on sample size or design (including both retrospective and prospective studies), and included crosssectional national surveys, as well as surveys from screening

programmes, antenatal clinics (ANC), blood donations, hospitals, and other institutions such as prisons. Papers that did not state sample size or HCV seroprevalence or identify the HCV diagnostic assays used were excluded. No study was discounted on the basis of HCV diagnostic assay; this review includes studies using both non-confirmatory (ELISA, EIA, screening assays) and confirmatory 6 Source: http://www.doksinet (RIBA, Western blots, PCR) assays. The prevalence of detectable HCV RNA prevalence was included where available. Search strategy References were identified from Medline and EMBASE (via Ovid). We searched for all papers that may contain HCV seroprevalence data in different population groups, the search strategy is shown in detail in Supplementary Table 1 and includes terms to assess the availability of data on HIV/HCV co-infection. Papers were included if published between 1st January 2002 and 31st December 2014 13. Data were extracted by one author (NJ) and verified in

full by another (VBR) on the following: country, year of publication, year of collection; study type, study design, HCV assay used, study population, sample size, proportion male, age, HCV seroprevalence, PCR prevalence, genotype (including percentage of each genotype where available), subtypes, and HIV co-infection prevalence. Cohort classification Cohorts were separated by either time of collection (if this was defined by the paper) or by collection site i.e ANC or Blood donor We also separated out control cohorts from intervention cohorts in 7 Source: http://www.doksinet case control studies. If there was a separate HIV sub-analysis within a study, this was included as a separate cohort within the HIV pooled prevalence but not counted overall as a separate cohort. Cohort studies were initially categorised as either low risk or high risk using definitions comparable with previous work 13. The low-risk category followed the definition from Madhava et al 13 , namely according

to the setting from which the samples were obtained and tested. The aggregated low risk group included (1) pregnant women at Antenatal Care (ANC), (2) blood donors and (3) other samples that were collected from the general population randomly selected communities whether rural or urban, students, and samples from inpatients or outpatients seeking care for nonhepatic illnesses or who had not had multiple blood transfusions . The high-risk group was divided into two groups: (1) patients suffering from known liver disease, whether acute or chronic; and (2) patients who had not been documented to have liver disease but who had high risk exposures such as multiple blood transfusions, haemodialysis, renal transplants, sickle-cell disease, or injecting drug use. HIV-infected cohorts were grouped separately to assess the prevalence of HIV and HCV co-infection. Data analysis 8 Source: http://www.doksinet Point estimates and 95% confidence intervals (CI) were calculated for the proportion of

people with HCV in each study. Prevalence of HCV by WHO region was estimated through pooling data from each study. Data were pooled using a DerSimonian-Laird random effects model 15 which incorporates an estimate of between-study variance, allowing that the true effect size may vary from study to study. 16 To assess between-study heterogeneity for the estimates of pooled prevalence by region, the τ2 statistic was calculated. The variance of raw proportions was stabilised using a Freeman-Tukey type arcsine square-root transformation. 17 Several methods of pooling proportions exist; the Freeman-Tukey method works well with both fixed-effects and random-effects meta-analysis. 18,19 Data were further stratified by risk group and HIV status. Analyses were conducted using STATA (v12, www.statacom) Role of the funding source There was no specific funding for this article. The corresponding author had full access to all the data and had final responsibility for the decision

to submit for publication. Results 9 Source: http://www.doksinet Search results 213 studies met eligibility criteria for inclusion identified from 33 countries in sub-Saharan Africa (Supplementary Figure 1; for all papers and references see Supplemental Table 6). These 213 studies included data on 287 cohorts comprising 1,198,167 individuals; 241 cohorts had sample sizes greater than 100. Most studies (177/213) were cross-sectional surveys; 15, were retrospective cohort studies and 19 were case-control studies. Testing methodology Of the 287 cohorts, 81 (28%) used confirmatory assays to screen for the presence of anti-HCV antibodies and HCV RNA. Less than 20% of the cohorts (55 of 287) described testing for HCV RNA (i.e reported HCV prevalence based on PCR testing). 39 cohorts presented data on HCV genotyping. Pooled seroprevalence The estimated pooled HCV seroprevalence across all 287 cohorts identified was 3% (95%CI: 2.9-31; τ2 006), varying widely between 7.8% (70 cohorts;

95%CI: 66-90; τ2 005) in the Central region to 4.5% (142 cohorts; 95%CI: 41-49; τ2 005) in West 10 Source: http://www.doksinet Africa and 0.8% (75 cohorts; 95%CI: 06-08; τ2 002) in Southern and Eastern (SE) Africa. 142/287 (49%) cohorts were collected in the West Africa region, but the majority of individuals included were from SE Africa skewed by a single survey from the South African Blood Service (732,250 samples) 20. Low-risk groups 185 cohorts studies (including 1,151,337 individuals) were identified as low-risk populations (Supplementary information Table 2) representing 30/33 countries. The pooled HCV seroprevalence among all low risk groups aggregated (defined above), across all regions of sub-Saharan Africa was 2.7% (95%CI: 2.5-28), Figure 1) This was higher than the pooled seroprevalence among all blood donor cohorts of 2% (95%CI: 1.92,1) but lower than the 69% (95%CI: 61-75) observed in other general population cohorts (1.8%, 95%CI: 16–18) There was

considerable regional variation among the low risk cohorts (Figure 1) with pooled HCV seroprevalence highest in the central African region (6.9%; 50 cohorts; 95% CI: 6-78) and lowest in SE Africa (0.7%; 35 cohorts; 95%CI: 07-078) West Africa 11 Source: http://www.doksinet contributed the largest number of cohorts (100) and most closely approaches the overall estimate. The pooled prevalence in aggregated low risk populations was a little higher than among blood donors (overall 2%, 76 cohorts; 95%CI: 1.9–21%), but this difference was most marked in the Central region with a seroprevalence amongst blood donors of 2.6% (19 cohorts; 95% CI: 17-36) The HCV pooled seroprevalence in the West Africa region among blood donors was 3.2% (95%CI: 28-36; 45 cohorts), and 04% (12 cohorts; 95%CI: 0.3-05) in SE Africa The highest HCV seroprevalence estimate in a blood donor cohort included in this analysis was 14.6% from a study that sampled blood donated at teaching hospitals and privately

owned blood banks in Nigeria (n=624)21. Among ANC populations, overall pooled HCV seroprevalence was 3% (21 cohorts; 95%CI: 2.2–38%), similar to the aggregated low risk cohort pooled estimate (Figure 1;). However, regional subanalysis, despite low cohort numbers, showed the ANC pooled HCV seroprevalence in Central Africa was again markedly lower (1.71; 95% CI: 13-22) than the overall Central region estimate in low risk populations. Pooled ANC seroprevalence in the West Africa (4.3%; 95%CI: 3-56) was higher than the Central Africa 12 Source: http://www.doksinet region SE Africa (pooled HCV seroprevalence of 0.4% (95%CI: 008) Finally a sub-analysis of the other 88 cohorts that were included in the low risk category, namely samples from the “general population” as well as inpatients and outpatients, not deemed to be a high risk of HCV, showed an overall pooled seroprevalence of 6.9% (95% CI: 61-77), ie higher than the estimates for ANC and Blood Donor populations. Regional

variation was marked with a pooled seroprevalence estimate in Central Africa of 12.1% (26 cohorts; 9.4-148) compared with 24% (21 cohorts; 96% CI: 1831) in SE region and 57% (41 cohorts; 95% CI: 47-68) in West Africa. In all regions, pooled estimates in these “other” low risk cohorts was higher than in ANC and Blood donor populations. High-risk groups 41 cohorts across 15 countries were categorised as high risk for HCV infection (20 from individuals with known liver disease, 21 from individuals transfusions, with injecting high-risk drug use, exposures, e.g haemodialysis, multiple healthcare workers, and prisoners), see Figure 2. The studies are detailed in Supplementary information table 3. 13 Source: http://www.doksinet Pooled HCV seroprevalence estimates across all 21 high-risk exposure cohorts were higher than those for low risk cohorts at 11.9% (95%CI: 71-167), with similar values across all regions (Figure 2). The estimates for high-risk cohorts in the Central

region (8.4; 95% CI: 51-118) was lower than the pooled seroprevalence estimate amongst “other” low risk cohorts for the same region, although cohort numbers are low. The highest HCV seroprevalence estimate identified through the literature review was recorded in Kenya in a sample population of 145 injecting drug users (46.2% HCV infected)22 In contrast, analysis of the 20 liver disease cohorts (Figure 2 ; Supplementary information table 3) found an overall pooled HCV seroprevalence estimate of 10% (95%CI: 6.8-131) Although similar levels of infection were estimated in West and SE regions, in the Central region the mean pooled seroprevalence of HCV among liver disease cohorts sampled was 2.5% (4 cohorts; 95%CI: 1.0-40) This is lower than estimates in this region for the aggregated low risk cohorts and in line with estimates for blood donor and ANC populations in the Central region. 14 Source: http://www.doksinet Our results suggest that whilst high-risk exposures may

result in a similar level of HCV infection across the regions of Africa, the proportion of liver disease caused by HCV varies significantly. HIV co-infection prevalence Seroprevalence of HCV/HIV co-infection was reported in 101 cohorts from 27 countries; some of which were recruited as HIV positive cohorts (61) and some identified as a sub-group within the primary analysis of each study. (A total of 42,648 HIV-positive individuals were included (Supplementary information table 3). 74% of cohorts (75/101) included more than 50 individuals. The overall pooled seroprevalence of HCV co-infection among HIV-infected individuals was estimated at 5.7% (95%CI: 49 - 66, Figure 3;). The majority of co-prevalence studies were from countries in the West Africa region (42 cohorts), with a pooled HCV seroprevalence of 6.7% (95%CI: 48-85 and SE Africa (43 cohorts) with a pooled HCV seroprevalence of 4.6% (95%CI: 3754) Estimates of co-infection in HIV-positive cohorts in all regions lie between those

for blood donor/ANC cohorts and high-risk cohorts. 15 Source: http://www.doksinet Some countries, e.g Senegal, Rwanda, Djibouti, and Gambia report relatively low HIV prevalence and low levels of co-infection (Figure 4). Some areas of high HIV prevalence, eg Malawi, Zimbabwe, and Zambia in southern Africa are estimated to have low HCV co-prevalence levels. The highest levels of co-prevalence are seen in East and South-East Africa (Tanzania, Mozambique, and Kenya) and Central Africa (Cameroon, Burundi, and Angola) of which only Mozambique reports HIV prevalence above 10%. Considering only countries with either a sample size greater than 500 HIV-positive patients or more than four HIV-positive cohorts, co-infection with HCV was estimated to be greater than mean seroprevalence of 10% in Burundi, Cameroon, Kenya, Mozambique, Tanzania, and Burkina Faso, and less than 5% in Uganda, Malawi, South Africa, and Côte d’Ivoire. 40 cohorts with 3422 HCV-infected individuals were

included, with pooled HIV prevalence of 15.9% (95%CI: 125-192) Regional breakdown revealed the highest rates of HIV co-infection in those with known HCV were in SE Africa (33.4%, 14 cohorts; 95%CI: 17.5-494) by contrast with West Africa (10%, 18 cohorts; 95%CI: 6.1-14) and Central Africa (59%, 8 cohorts; 95%CI: 25-93) Confirmatory and molecular testing 16 Source: http://www.doksinet Only 52/185 low risk cohorts employed confirmatory assays to screen for the presence of anti-HCV antibodies. The mean estimates for pooled HCV seroprevalence overall and in each of the regions were not significantly different to those found from all general population cohorts when restricted to those with confirmatory assays. Analysis of the 35 low risk cohorts that also reported PCR testing revealed the pooled mean proportion of positive serology samples that were PCR positive was 49.5% (95%CI: 403-589) (Figure 5) Data for the genotype distribution of HCV was reported for only 39 cohorts in 19

countries. Discussion We have estimated the pooled seroprevalence of HCV infection in sub-Saharan Africa to be 3% (95%CI: 2.9-31) when all samples were analysed collectively, and 2.7% (95%CI: 25-28) when limited to ‘low risk” samples in line with previous definitions. We identified regional variation among groups considered “low risk”, with the highest pooled seroprevalence calculated within the Central Africa region. In all regions, the estimates of HCV 17 Source: http://www.doksinet seroprevalence were lower among blood donor cohorts and ANC groups than within aggregated low risk cohorts. However the regional and overall pooled seroprevalences in the “other” low risk groups were higher. These cohorts included individuals in healthcare settings as part of case control studies or convenience sampling. Such settings are known to be associated with transmission of HCV due to potential nosocomial transmission through fomites or non-exposure prone procedures including

venepuncture and cannulation14,24-26 and may explain why observed prevalences are higher than in population surveys. The overall estimates for HCV seroprevalence are very similar to those described previously, despite the estimates being based on different studies and different time periods [13] {Madhava, 2002 #396}. This gives more confidence on the robustness of these estimates and suggests no major change in HCV prevalence between the periods of study. However, larger population surveys, repeated over time, are required to monitor these trends. Given that population surveys are time consuming and expensive, other complementary methods are required to monitor changes in prevalence. The observation that HCV prevalences in antenatal cohorts are similar to those in the overall population suggests 18 Source: http://www.doksinet antenatal surveillance may represent a useful population for monitoring, particularly as there are many existing programmes testing for HIV in this group.

Earlier analyses conducted as the HIV epidemic took hold in subSaharan Africa found little evidence of association between the prevalence of HIV and HCV infections13. More recently, an increased relative risk of HBV and HCV infection has been reported in HIV-positive compared with HIV-negative populations 14 . We found the overall the seroprevalence of HCV infection in HIV-infected individuals was significantly higher than in blood donor or ANC groups and similar to defined general population cohorts (6.2%), a finding consistent across all regions The highest estimates of HCV/HIV co-infection occurred in countries (Tanzania, Burkina Faso, Cameroon, and Kenya) with moderate reported adult HIV prevalence (all, except Mozambique, less than 6%). By contrast, countries with the highest HIV prevalence (South Africa, Botswana, Zimbabwe, Zambia, Mozambique, and Malawi) were all estimated to have low to moderate levels of HCV co-infection (less than 5%), again excepting Mozambique.

Conversely, we found an increased seroprevalence of HIV co-infection in those identified as HCV 19 Source: http://www.doksinet seropositive, except in the Central region although, again, our analysis included fewer cohorts and samples from the Central region than from SE or West Africa. These differences suggest that risk behaviours responsible for HCV transmission might be quite dissociated from those associated with HIV transmission in some regions, for example Central Africa. It is also possible that regional differences are in part explained by risk behaviours that are specific to one area (e.g scarification or specific medical practices) but we did not find large studies that were able to explore this hypothesis further. Although our meta-analysis of HIV/HCV co-infection is the largest to date, it is limited by the geographic distribution of the papers identified through the systematic review. While the majority of reported studies were from the West Africa region, most samples

were from SE Africa, especially South Africa (including one large population survey). Nonetheless, the data here support the need for provision of HCV testing and care in all HIV programmes and developing programmes for HCV infection. Despite retrieving a large number of studies, we limited our review to published articles retrieved from searching two databases and published in two languages; it is possible that an expanded search including grey 20 Source: http://www.doksinet literature and additional languages (notably Arabic and Portuguese) would have contributed additional studies. The quality of studies included was variable since the great majority were not cross-sectional population-based surveys, but instead targeted specific groups in limited geographic regions. All the studies assessed HCV infection through serology, a proportion going on to perform confirmatory testing. The results of the PCR testing suggest the numbers of seropositive patients who have active

disease, and hence require treatment, is around half. The extent to which this is a result of false-positive serology, a wellrecognised challenge, is hard to quantify. However, a sub-analysis restricted to those general population samples with confirmed serology found prevalence similar to that in all general population samples, suggesting this was not a major issue. It is important to recognise that a large proportion of seropositive individuals will not require treatment and this data reinforces the need for larger community surveys with high quality diagnostic methodology including HIV and HCV nucleic acid testing for more robust prevalence estimates to inform development of prevention and treatment programmes. Conclusions 21 Source: http://www.doksinet Our systematic review and meta-analysis found a high seroprevalence of HCV across populations of sub-Saharan Africa including within HIV-positive adults, with evidence of regional variation in the general population. There are

limitations to available data with a need for larger survey studies, but monitoring antenatal HCV prevalence may be a helpful indicator of trends in HCV infection. Regardless, there is clear unmet need for prevention and treatment, access to which needs to be improved for both mono-infected and co-infected individuals. Contributors The study was designed by GC and NF. Analysis was done by NJ, BR, JM, NF, and GC. The first draft was written by BR and GC; all authors contributed to the final manuscript and approved the final version of the manuscript before submission. Declaration of interests GC has been an investigator on trials of HCV therapy sponsored by Boeringher-Ingelheim, Gilead, Merck and Bristol-Myers Squibb. GC has acted in an advisory role to Merck, Boeringher-Ingelheim, Gilead, Janssen and WHO in relation to viral hepatitis. 22 Source: http://www.doksinet Acknowledgements GC is supported in part by the Biomedical Research Centre of Imperial College NHS Trust and the MRC

STOP HCV consortium. Sarah Venis of MSF UK provided editing assistance, Theo Cooke and Fred Cooke assistance with data collection. 23 Source: http://www.doksinet 24 Source: http://www.doksinet Figure Legends Figure 1: Forest plot of estimated HCV pooled seroprevalence in low risk populations (i) All low risk cohorts aggregated (ii) Blood donor cohorts (iii) Antenatal clinic cohorts and (iv) All Other low risk cohorts – general population, inpatients and outpatients Figure 2: Forest plot of estimated HCV pooled seroprevalence in high risk populations (i) All high risk cohorts aggregated (ii) Patients presenting with liver disease Figure 3 (i) Seroprevalence of HCV in HIV positive cohorts and (ii) Seroprevalence of HIV in HCV positive cohorts , both separated by region Figure 4: Estimated HCV seroprevalence in HIV positive cohorts in relation to HIV prevalence in 15-49 year olds [HIV data from WHO/UNAIDS 2013) Figure 5: Forest plot of estimated HCV seroprevalence in 35 low risk

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